A fundamental hypothesis of this Center is that a disruption in glutamatergic function is a primary mechanism underlying the pathology in schizophrenia. This dysfunction leads to an imbalance of dopamine transmission in cortex and striatum. In rodents, a primary source of glutamate to the dopamine neurons is from cortex. However, our preliminary results demonstrate few cortical fibers from specific prefrontal regions terminate in the region of the primate midbrain dopamine system. In addition to a descending cortical pathway, other potential sources of glutamate input to the midbrain include the subthatamic nucleus the zona incerta and the penduculo-pontine nucleus. The first goal of the proposed studies is to identify candidate structures tliat may play a major role in the glutamatergic regulation of the midbrain dopamine cells. Dopamine fibers project densely to cortex, terminating in both superficial mad deep layers. These fibers are in a position to modulate descending projections to subcortical areas, including the striatum, the subthalamic nucleus and the zona incerta. These subcortical structures can, in turn exert a modulatory influence on dopamine.l The second goal of the proposed studies is to determine whether dopamine terminals in cortex are found: in proximity to cells projecting to the striatum, subthalamic nucleus and the zona inCerta. Overall this project is designed to develop a more comprehensive understanding of the topography of cortical-DA interactions in the primate brain. The proposed studies will test the hypothesis that glutamatergic control of dopamine in primates occurs through a convergence of complex cortico-subcortical pathways. Furthermore, dopamine fibers in cortex may play a role in that control.